In lung cancer, vasoactive intestinal peptide (VIP) and the structurally related pituitary adenylate cyclase releasing polypeptide (PACAP) are autocrine growth factors. PACAP binds with high affinity to lung cancer cells, elevates cAMP as well as cytosolic Ca2+ and stimulates growth. In the present period, PACAP was found to elevate c-fos and c-myc mRNAs in lung cancer cells. The effects were concentration and time dependent being maximal 1 hour after addition of 100 nM PACAP-27. Similar effects were observed for PACAP-38 but not PACAP(28-38) which was inactive. PACAP(6-38) had no effects on basal c-fos mRNA but antagonized the increase caused by PACAP-27 or PACAP-38. These data suggest that the increase in nuclear oncogene expression caused by PACAP-27 may regulate lung cancer proliferation. In breast cancer, VIP-1 receptors were identified in cell lines and biopsy specimens. All cell lines tested bound 125I-VIP with high affinity and had VIP-1 receptor mRNA. VIP (10 nM) elevated cAMP 10-fold and VIPhybrid antagonized the increase in cAMP caused by VIP. VIP transiently elevated c-fos or c-myc mRNA and the increase caused by VIP was antagonized by VIPhybrid. VIPhybrid decreased MCF-7 or MDA-MB231 colony growth in vitro. In vivo, VIPhybrid slowed MCF-7 or MDA-MB231 xenograft growth using nude mice. Using in vitro autoradiography techniques, 125I-VIP bound with high affinity to sections derived from frozen breast cancer biopsy specimens and radiolabeled VIP binding was inhibited by VIPhybrid. These data suggest that VIPhybrid may be a therapeutic agent for NSCLC. Bombesin/gastrin releasing peptide (BB/GRP) and insulin-like growth factor I (IGF-I) receptors were detected in non-small cell lung cancer (NSCLC) cell lines. (125I-Tyr4)BB bound with high affinity to NCI-H1299 cells and specific binding was inhibited with high affinity by BB or BW2258U89. BW2258U89 antagonized the increase in cytosolic Ca2+ caused by 10 nM BB. BW2258U89 decreased and BB increased NCI-H1299 colony growth in soft agar. These data suggest that BW2258U89 is a GRP receptor antagonist and monoclonal antibody (MAb) alphaIR-3 may be an IGF-I receptor antagonist. 125I-alphaIR-3 binding to NSCLC cells was inhibited with high affinity by alphaIR-3 or IGF-I. MAb alphaIR-3 immunoprecipitated 90 and 135 KDalton proteins which represent subunits of the IGF-I receptor. MAb alphaIR-3 inhibited the growth of NSCLC in vitro and in vivo. These data suggest that NSCLC cells have GRP and IGF-I receptors.